The new frontier of bone formation: A breakthrough in postmenopausal osteoporosis

Climacteric

Volumn 12, Issue 4, 2009, Pages 286-300

  Ruiz, C ^a   Abril, N ^a   Tarn, J J ^b   Garcia Perez M A ^b   Cano, A ^b  

^a Hospital Clnico Universitario   (Spain)

^b UNIVERSITY OF VALENCIA   (Spain)

Author keywords

Bone formation; Osteoblastogenesis; Parathyroid hormone; Postmenopausal osteoporosis; Strontium ranelate

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; ALENDRONIC ACID; BONE MORPHOGENETIC PROTEIN 2; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; FIBROBLAST GROWTH FACTOR 2; FOLLITROPIN; INTERLEUKIN 6; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 5; MITOGEN ACTIVATED PROTEIN KINASE; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; PARATHYROID HORMONE; PARATHYROID HORMONE RECEPTOR 1; PARATHYROID HORMONE[1-34]; PLACEBO; PROTEIN KINASE C; RALOXIFENE; SCLEROSTIN; SOMATOMEDIN BINDING PROTEIN; SOMATOMEDIN C; STRONTIUM RANELATE; TRANSCRIPTION FACTOR DLX5; TRANSCRIPTION FACTOR MSX2; TRANSCRIPTION FACTOR OSTERIX; TRANSCRIPTION FACTOR RUNX2; TRANSFORMING GROWTH FACTOR BETA; VITAMIN D;

APOPTOSIS; BONE DENSITY; BONE DEVELOPMENT; BONE MASS; BONE METABOLISM; BONE STRENGTH; CELL DIFFERENTIATION; CELL SURVIVAL; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; DIARRHEA; DRESS SYNDROME; DRUG EFFICACY; DRUG ERUPTION; DRUG INDUCED HEADACHE; GENE EXPRESSION; HUMAN; HYPERCALCEMIA; LUNG EMBOLISM; MENOPAUSE; NAUSEA; NONHUMAN; OSSIFICATION; OSTEOBLAST; OSTEOLYSIS; POSTMENOPAUSE OSTEOPOROSIS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; STIMULATION; VEIN THROMBOSIS; VERTEBRA FRACTURE;

AGED; ANIMALS; BONE DENSITY CONSERVATION AGENTS; CELL DIFFERENTIATION; FEMALE; FRACTURES, BONE; GENE EXPRESSION REGULATION; HUMANS; MIDDLE AGED; ORGANOMETALLIC COMPOUNDS; OSTEOBLASTS; OSTEOGENESIS; OSTEOPOROSIS, POSTMENOPAUSAL; PARATHYROID HORMONE; THIOPHENES;

EID: 70350610911     PISSN: 13697137     EISSN: 14730804     Source Type: Journal    
DOI: 10.1080/13697130902736939     Document Type: Review

References (119)

1. Seeman E, Delmas PD. Bone quality - the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-2261
2. Lips P, Courpron P, Meunier PJ. Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res 1978;26:13-17
3. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333
4. http://www.fda.gov/cder/drug/infopage/estrogens-progestins/QA.htm (accessed on November 24th, 2008)
5. http://www.emea.europa.eu/pdfs/human/press/ pus/3306503en.pdf (accessed on November 24th, 2008)
6. http://www.imsociety.org/pdf-files/comments- and-press-statements/ims- press-statement- 13-05-08.pdf (accessed on November 24th, 2008)
7. Keen R. Osteoporosis: strategies for prevention and management. Best Pract Res Clin Rheumatol 2007;21:109-122
8. Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 2007;40:1434-1446
9. Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodelling after fatigue in vivo. J Bone Miner Res 2000;15:60-67
10. Colopy SA, Benz-Dean J, Barrett JG, et al. Response of the osteocyte syncytium adjacent to and distant from linear microcracks during adaptation to cyclic fatigue loading. Bone 2004;35:881-891
11. Noble BS. The osteocyte lineage. Arch Biochem Biophys 2008;473:106-111
12. Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature 2003;423:349-355
13. Ducy P, Zhang R, Geoffroy V, et al. Osf2/ Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997;89:747-754
14. Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997;89:755-764
15. Otto F, Thornell AP, Crompton T, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997;89:765-771
16. Takeda S, Bonnamy JP, Owen MJ, et al. Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev 2001;15:467-481
17. Nakashima K, Zhou X, Kunkel G, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002;108: 17-29
18. Nishio Y, Dong Y, Paris M, et al. Runx2- mediated regulation of the zinc finger Osterix/ Sp7 gene. Gene 2006;372:62-70
19. Xiao G, Jiang D, Ge C, et al. Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem 2005;280:30689-30696
20. Yang X, Matsuda K, Bialek P, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin- Lowry Syndrome. Cell 2004;117:387-398
21. Marie PJ. Transcription factors controlling osteoblastogenesis. Arch Biochem Biophys 2008;473:98-105
22. Reeve J, Meunier PJ, Parsons JA, et al. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. Br Med J 1980;280:1340-1344
23. Ma YL, Zeng Q, Donley DW, et al. Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis. J BoneMiner Res 2006;21:855-864
24. Lindsay R, Zhou H, Cosman F, et al. Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res 2007;22:495-502
25. Pickard BW, Hodsman AB, Fraher LJ, et al. Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: association of PTH1R with importin alpha1 and beta. Endocrinology 2006;147:3326-3332
26. Pettway GJ, Meganck JA, Koh AJ, et al. Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation. Bone 2008;42:806-818
27. Krishnan V, Moore TL, Ma YL, et al. Parathyroid hormone bone anabolic action requires Cbfa1/Runx2-dependent signaling. Mol Endocrinol 2003;17:423-435
28. Qin L, Li X, Ko JK, et al. Parathyroid hormone uses multiple mechanisms to arrest the cell cycle progression of osteoblastic cells from G1 to S phase. J Biol Chem 2005;280:3104-3111
29. Ma YL, Cain RL, Halladay DL, et al. Catabolic effects of continuous human PTH (1-38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 2001;142:4047-4054
30. Huang JC, Sakata T, Pfleger LL, et al. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 2004;19:235-244
31. Samadfam R, Xia Q, Goltzman D. Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice. J Bone Miner Res 2007;22:55-63
32. Delmas PD, Vergnaud P, Arlot ME, et al. The anabolic effect of human PTH (1-34) on bone formation is blunted when bone resorption is inhibited by the bisphosphonate tiludronate - is activated resorption a prerequisite for the in vivo effect of PTH on formation in a remodeling system? Bone 1995;16:603-610
33. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349: 1207-1215
34. Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003;349:1216-1226
35. Manolagas SC, Kousteni S, Jilka RL. Sex steroids and bone. Rec Prog Horm Res 2002; 57:385-409
36. Nakamura T, Imai Y, Matsumoto T, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 2007;130:811-823
37. Bord S, Horner A, Beavan S, et al. Estrogen receptors alpha and beta are differentially expressed in developing human bone. J Clin Endocrinol Metab 2001;86:2309-2314
38. Kousteni S, Han L, Chen JR, et al. Kinasemediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest 2003;111:1651-1664
39. Ogita M, Rached MT, Dworakowski E, et al. Differentiation and proliferation of periosteal osteoblast progenitors are differentially regulated by estrogens and intermittent PTH administration. Endocrinology 2008;149: 5713-5723
40. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000;21:115-137
41. Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 1994;8:133-146
42. Sakou T. Bone morphogenetic proteins: from basic studies to clinical approaches. Bone 1998;22:591-603
43. Lee KS, Kim HJ, Li QL, et al. Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol Cell Biol 2000;20:8783-8792
44. Geusens PP, Boonen S. Osteoporosis and the growth hormone-insulin-like growth factor axis. Horm Res 2002;58(Suppl 3):49-55
45. Conover CA. Insulin-like growth factor-binding proteins and bone metabolism. Am J Physiol Endocrinol Metab 2008;294:E10-4
46. Le Roith D. Regulation of proliferation and apoptosis by the insulin-like growth factor I receptor. Growth Horm IGF Res 2000; 10: S12-S13
47. Mohan S, Baylink DJ. Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences. J Endocrinol 2005;185:415-420
48. Mohan S, Richman C, Guo R, et al. Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormonedependent and -independent mechanisms. Endocrinology 2003;144:929-936
49. Langlois JA, Rosen CJ, Visser M, et al. Association between insulin-like growth factor I and bone mineral density in older women and men: the Framingham Heart Study. J Clin Endocrinol Metab 1998;83:4257-4262 (Pubitemid 29100118)
50. Garnero P, Sornay-Rendu E, Delmas PD. Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women. Lancet 2000;355:898-899
51. Canalis E, Centrella M, Burch W, et al. Insulinlike growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 1989;83:60-65
52. Miyakoshi N, Kasukawa Y, Linkhart TA, et al. Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology 2001;142:4349-4356
53. Zhao G, Monier-Faugere MC, Langub MC, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 2000;141:2674-2682
54. Jiang J, Lichtler AC, Gronowicz GA, et al. Transgenic mice with osteoblast-targeted insulin-like growth factor-I show increased bone remodeling. Bone 2006;39:494-504
55. Zhang M, Xuan S, Bouxsein ML, et al. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem 2002;277:44005-44012
56. Govoni KE, Wergedal JE, Florin L, et al. Conditional deletion of insulin-like growth factor-I in collagen type 1alpha2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion. Endocrinology 2007;148:5706-5715
57. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signalling. J Clin Invest 2006;116:1202-1209
58. Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant highbone- mass trait. Am J Hum Genet 2002;70:11-19
59. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptorrelated protein 5. N Engl J Med 2002;346: 1513-1521
60. Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005;280:19883-19887
61. MacDonald BT, Joiner DM, Oyserman SM, et al. Bone mass is inversely proportional to Dkk1 levels in mice. Bone 2007;41:331-339
62. Balemans W, Piters E, Cleiren E, et al. The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif Tissue Int 2008;82: 445-453
63. Morvan F, Boulukos K, Clément-Lacroix P, et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 2006;21:934-945
64. Li J, Sarosi I, Cattley RC, et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 2006;39:754-766
65. Brunkow ME, Gardner JC, Van Ness J, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knotcontaining protein. Am J Hum Genet 2001;68: 577-589
66. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 2008;283:5866-5875
67. Balemans W, Ebeling M, Patel N, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 2001;10:537-543
68. Balemans W, Patel N, Ebeling M, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 2002;39:91-97
69. Staehling-Hampton K, Proll S, Paeper BW, et al. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 2002;110:144-152
70. van Bezooijen RL, Svensson JP, Eefting D, et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 2007; 22:19-28
71. Sims NA, Jenkins BJ, Quinn JM, et al. Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J Clin Invest 2004;113:379-389
72. Franchimont N, Wertz S, Malaise M. Interleukin- 6: an osteotropic factor influencing bone formation? Bone 2005;37:601-606
73. Thomas T, Gori F, Khosla S, et al. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 1999;140:1630-1638
74. Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100:197-207
75. Takeda S, Karsenty G. Molecular bases of the sympathetic regulation of bone mass. Bone 2008;42:837-840
76. Williams GR. Hypogonadal bone loss: sex steroids or gonadotropins? Endocrinology 2007;148:2610-2612
77. Sun L, Peng Y, Sharrow AC, et al. FSH directly regulates bone mass. Cell 2006;125:247-260
78. Xu ZR, Wang AH, Wu XP, et al. Relationship of age-related concentrations of serum FSH and LH with bone mineral density, prevalence of osteoporosis in native Chinese women. Clin Chim Acta 2009;400:8-13
79. Castelo-Branco C, León M, Durán M, et al. Follicle-stimulating hormone does not directly regulate bone mass in human beings: evidence from nature. Fertil Steril 2008;90:2211-2216
80. Marie PJ, Ammann P, Boivin G, et al. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int 2001;69: 121-129
81. Canalis E, Hott M, Deloffre P, et al. The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone 1996;18:517-523
82. Bonnelye E, Chabadel A, Saltel F, et al. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone 2008;42:129-138
83. Zhu LL, Zaidi S, Peng Y, et al. Induction of a program gene expression during osteoblast differentiation with strontium ranelate. Biochem Biophys Res Commun 2007;355:307-311
84. Buehler J, Chappuis P, Saffar JL, et al. Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis). Bone 2001;29: 176-179
85. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res 2008;23:215-222
86. Chattopadhyay N, Quinn SJ, Kifor O, et al. The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. Biochem Pharmacol 2007;74: 438-447
87. Pi M, Quarles LD. A novel cation-sensing mechanism in osteoblasts is a molecular target for strontium. J Bone Miner Res 2004;19: 862-869
88. Pi M, Faber P, Ekema G, et al. Identification of a novel extracellular cation-sensing G-proteincoupled receptor. J Biol Chem 2005;280: 40201-40209
89. Choudhary S, Halbout P, Alander C, et al. Strontium ranelate promotes osteoblastic differentiation and mineralization of murine bone marrow stromal cells: involvement of prostaglandins. J Bone Miner Res 2007;22:1002-1010
90. Choudhary S, Wadhwa S, Raisz LG, et al. Extracellular calcium is a potent inducer of cyclo-oxygenase-2 in murine osteoblasts through an ERK signaling pathway. J Bone Miner Res 2003;18:1813-1824
91. Boissy P, Andersen TL, Abdallah BM, et al. Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 2005;65: 9943-9952
92. Nyan M, Sato D, Oda M, et al. Bone formation with the combination of simvastatin and calcium sulfate in critical-sized rat calvarial defect. J Pharmacol Sci 2007;104:384-386
93. Carpizo KH, Saran MJ, Huang W, et al. Pretreatment of poly(l-lactide-co-glycolide) scaffolds with sodium hydroxide enhances osteoblastic differentiation and slows proliferation of mouse preosteoblast cells. Plast Reconstr Surg 2008;121:424-434
94. Chang HH, Wu CB, Chen YJ, et al. MMP-3 response to compressive forces in vitro and in vivo. J Dent Res 2008;87:692-696
95. Wu JB, Fong YC, Tsai HY, et al. Naringininduced bone morphogenetic protein-2 expression via PI3K, Akt, c-Fos/c-Jun and AP-1 pathway in osteoblasts. Eur J Pharmacol 2008;588:333-341
96. Suzuki N, Somei M, Seki A, et al. Novel bromomelatonin derivatives as potentially effective drugs to treat bone diseases. J Pineal Res 2008;45:229-234
97. Do SH, Lee JW, Jeong WI, et al. Boneprotecting effect of Rubus coreanus by dual regulation of osteoblasts and osteoclasts. Menopause 2008;15:676-683
98. Zhao Y, Li J, Liu Y, et al. Gu Ling Pian, a traditional Chinese medicine, regulates function and OPG/RANKL synthesis of osteoblasts via the p38 MAPK pathway. J Pharm Pharmacol 2007;59:1167-1173
99. Bhattacharya A, Banu J, Rahman M, et al. Biological effects of conjugated linoleic acids in health and disease. J Nutr Biochem 2006;17: 789-810
100. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357:2028-2039
101. Lane NE, Sanchez S, Modin GW, et al. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 1998;102:1627-1633
102. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441
103. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007;146:326-339
104. Antoniucci DM, Sellmeyer DE, Bilezikian JP, et al. Elevations in serum and urinary calcium with parathyroid hormone (1-84) with and without alendronate for osteoporosis. J Clin Endocrinol Metab 2007;92:942-947
105. Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87:4528-4535
106. Rittmaster RS, Bolognese M, Ettinger MP, et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 2000; 85:2129-2134
107. Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 2005;353:555-565
108. Arlot M, Meunier PJ, Boivin G, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res 2005;20:1244-1253
109. Barbehenn EK, Lurie P, Wolfe SM. Osteosarcoma risk in rats using PTH 1-34. Trends Endocrinol Metab 2001;12:383
110. http://www.fda.gov/ohrms/dockets/ac/01/briefing/ 3761b2-05-PharmTox.htm (accessed on November 24th, 2008)
111. Meunier PJ, Slosman DO, Delmas PD, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis - a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab 2002; 87:2060-2066
112. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350: 459-468 (Pubitemid 38133766)
113. Blake GM, Fogelman I. The correction of BMD measurements for bone strontium content. J Clin Densitom 2007;10:259-265
114. Roux C, Fechtenbaum J, Kolta S, et al. Strontium ranelate reduces the risk of vertebral fracture in young postmenopausal women with severe osteoporosis. Ann Rheum Dis 2008;67: 1736-1738
115. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90:2816-2822
116. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: results of a five-year, randomized, placebocontrolled trial. Arthritis Rheum 2008;58: 1687-1695
117. http://www.emea.europa.eu/humandocs/PDFs/ EPAR/protelos/PressRelease- Protelos-417458 07en.pdf (accessed on November 24th, 2008)
118. http://www.emea.europa.eu/humandocs/PDFs/ EPAR/protelos/121604en6.pdf. (accessed on November 24th, 2008)
119. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res 2007;22:1832-1841